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Pramiracetam

Pramiracetam is a well-known nootropic agent that belongs to the highly effective family of Nootropics known as Racetams. A nootropic is a substance that can be used to improve cognitive and mental functions. Pramiracetam is a lipid-soluble Racetam due to its “pyrrolidone nucleus”. The substance has a high affinity for choline uptake, and its chemical structure is similar to that of Aniracetam although it is 15-30 times more potent than Aniracetam. Its efficacy sets it apart from other racetams for it works effectively even in lower dosages, and its half-life is longer than that of Aniracetam. The molecular formula for Pramiracetam is; C14H27N3O2, C14H27N3O2.H2SO4. Its chemical names are N-[2-(diisopropylamine) ethyl]-2-(2-oxopyrrolidin-1-yl)acetamide, N-[2-bis(1-methylethyl)amino]ethyl]-2-oxo-1-pyrrolidineacetamide and popular code name is CI-879. Compared to other racetams, Pramiracetam is the most lipophilic and this makes its absorption through the lipid bilayers the most rapid.

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HISTORY

Pramiracetam was discovered in the late 1970’s by scientists at Park-Davis & Co (at the time a division of Warner-Lambert but currently a subsidiary of Pfizer) in Belgium. The first patents for this nootropic were issued in Belgium in 1978 and the U.S. in 1979. The substance is a Racetam molecule, and it was originally synthesized from Piracetam in 1984 because its modifications were noted to have more anti-amnesiac effects in rats. In its preparation from Piracetam, the amide group is replaced with a dipropan-2-ylaminoethyl group. The substance has undergone significant and thorough research in the last four decades, and it is widely accepted as one of the top Nootropics under commercial production. The substance is promoted by Menarini using the brand name Pramistar.

Since its discovery in the 1970s, Pramiracetam has been intensely researched. Discovered by scientists at Parke-Davis & Co, a division of Warner-Lambert at the time, clinical trials were conducted in Alzheimer’s disease but were terminated after Phase II trials gave mixed results. It was henceforth developed as an orphan drug. It’s at this time that Warner-Lambert licensed its European rights to Menarini, and the substance was produced specifically for dementias. Later in 1991, it licensed Cambridge Neuroscience, Inc. (CNI) for U.S. and non-European rights. CNI carried out a clinical trial involving four individuals with cognitive problems after head injuries. The trials carried out by or on behalf of Warner-Lambert and Menarini consisted of two small trials that were conducted in Ukraine. One study focused on individuals with the cerebrovascular disease while the other study was based on persons with a concussion. Another clinical trial although small was conducted in Italy, and its subjects were healthy individuals who had amnesia induced in them using scopolamine.

CLINICAL STUDIES

Numerous scientific studies have been performed to establish the potential of Pramiracetam to be an effective therapy for Alzheimer’s, senile dementia, and concussions. Clinical trials have indicated some particular therapeutic activities influenced by modifications of the cognitive functions. An improvement was observed in long-term memory, learning, concentration, attention span, alertness, and in the rate of high-affinity choline take up in the hippocampus. A study that involved the use of a placebo-controlled experiments in an attempt to established if this particular nootropic agent was capable of assisting improve delayed recall and memory in young men who had cognitive and memory problems as a result of anoxia or severe head injury was conducted in 1991. A dose of Pramiracetam (comparable to that of 400mg of sulfate) taken thrice in a day over a period of one and a half years of therapy and one month after terminating use. This particular study also proved that Pramiracetam was safe and very effective during the 18 months period of administering the medication and even a month after its use was terminated. A study involving subjects who comprised of elderly individuals suffering from memory loss, administration of Pramiracetam within a period of 12 weeks was observed to enhance objective memory retention to a larger extent than memory training that involved 90 minutes of weekly training with tutors. Pramiracetam is said to raise acetylcholine levels in the brain and this results in increased blood flow to the brain hence brain productivity is enhanced. When healthy volunteers were administered with scopolamine after ten days of taking Pramiracetam supplements of 600mg twice per day, the prior Pramiracetam therapy helped them to reverse the amnesiac effects caused by scopolamine on selective attention and episodic memory tests. Despite the limited supporting evidence in both young individuals with brain injuries and older men with memory loss, Pramiracetam seems to have nootropic potential when orally ingested (standard supplemental dosage in humans). In animal studies, evidence shows that old and healthy young rats tend to experience benefits to their long-term memory formation after administration of Pramiracetam supplements. Its effectiveness was observed to peak after it was taken acutely within 1-2 hours prior to the cognitive tests and there were no observed effects on working memory.

Animal studies that used aged lab rats as study subjects showed that Pramiracetam was able to restore the alterations that had occurred in their EEG function to a state observed in youthful rats when administered in the range of 5-20mg/kg. The results showed that the efficiency of 5-200mg/kg Pramiracetam exceeded that of 200-400mg/kg Piracetam. Significant alterations in the brain wave function have been observed in healthy rats administered with Pramiracetam and the degree of changes observed in the hippocampal theta waves and cortical slow waves correlated to the cognitive improvement in a water maze test. Pramiracetam seems to significantly influence EEG readings in both young and elderly rats, but the mechanisms that explain these alterations are not yet clearly established.

Another study was focusing on the potential of Pramiracetam to cause effects on cholinergic neurotransmission was carried out. The study showed that an intraperitoneal injection of Pramiracetam in the range of 44-88mg/kg to rats was able to improve HACU (high-affinity choline uptake) in their hippocampal slices in just 30 minutes. This effect was not observed for Aniracetam and Piracetam whereby small doses of 8.8mg/kg and larger doses of 176mg/kg had no observable changes. Pramiracetam has also been seen to normalize the alterations stimulated by scopolamine on the transport of choline. However, when tried in vitro, direct administration of Pramiracetam to hippocampal slices in youthful rats was not able to increase HACU. As such, Pramiracetam may be in a position to improve high-affinity choline uptake (HACU), the rate that limits acetylcholine synthesis.

A study conducted to test the impact of Pramiracetam on memory and cognition in animals showed significant potency. The study focusing on the anti-amnesiac potential of the substance demonstrated that the amnesia-reversal potential after intraperitoneal injection had peak efficacy of 96% at 5mg/kg. It also revealed that Pramiracetam had a higher potency than Piracetam, and this was the basis used to synthesize Pramiracetam. Additionally, pre-administration of Pramiracetam can suppress amnesia caused by the anticholinergic toxin hemicholinium-3. Note that amnesiac studies based on animals have limited evidence although they indicate that Pramiracetam is more potent than Piracetam.

A clinical study carried out to test the effect of Pramiracetam in individuals suffering from Alzheimer’s disease failed to establish any evidence that the substance brought about efficiency. The dosage for each patient was chosen in the range of 1,200-4,000mg per day based on what the subject showed the best response. The results indicated that Pramiracetam may not have therapeutic effects on Alzheimer’s condition. Up to date, there is no viable evidence to support the use of Pramiracetam in lowering the symptoms and pathology of Alzheimer’s condition. It is alleged that Pramiracetam has numerous positive effects in most users even in those suffering from ADHD and ADD.

Another study compared the effects of Pramiracetam against those of kynurenic acid and administration of 30mg/kg of Pramiracetam resulted in enhanced object recognition memory. There are other cases in which improvements in object recognition observed with 30mg/kg of Pramiracetam were more effective than in 15mg/kg and 60mg/kg of Pramiracetam when compared to 400mg/kg of Piracetam. In tests involving step-down avoidance, the improvement was observed in mice that had oral Pramiracetam of 100mg/kg within 1-2 hours preceding the trial. The tests compared the efficacy of Pramiracetam to Oxiracetam of the same dose, and the results showed that both either performed better than or outperformed Aniracetam and they also outperformed Piracetam. Water maze performance was noted to significantly improve with just a single trial. A dose of 10mg/kg seemed to be most effective than doses that are lower or higher.

When administered in rats through intraperitoneal injections at a range of 7.5-15mg/kg within seven weeks of training using a radial maze task, enhancements were noted in long-term reference memory, and no effects were observed in the case of working memory. In most instances, the 15mg/kg dosage proved to be more efficient than the 7.5mg/kg although the difference was not significant. As such, Pramiracetam has been proven to help long-term memory formation but it has no effects on working memory. Its efficiency in research animals has been observed after acute use before the cognitive testing.

The main drug regulating agencies in the U.S. such as US Food and Drug Administration (FDA) neither evaluated nor approved human consumption of Pramiracetam as there is limited statistical data to prove that it is effective as the manufacturers explain.